This invention relates to a novel process for preparing hydroxypyrrolidinyl ethylamine compounds and their pharmaceutically acceptable salts. The pharmaceutically active compounds prepared by the process of this invention can be used as selective kappa-receptor agonists.
Opioid analgesics such as morphine are therapeutically useful, but their usage is strictly limited because of their side effects such as drug dependency and abuse. Thus, analgesics with high usefulness and reduced tendency to cause drug dependency are desired. Considerable pharmacological and biochemical studies have been carried out to discover the opioid peptides and opioid receptors, and the discovery of the subtype of opioid receptor such as mu (xcexc), delta (xcex4), kappa (xcexa) in a variety of species, including human, has made a beginning towards creating new analgesics. As it is thought that opioid analgesics such as morphine act as a mu-receptor agonist, separating the action based on a kappa-receptor agonist from the action based on mu-receptor agonist has been investigated. Recently kappa-selective agonists (kappa-agonists) have been reported from the above viewpoint for example, EMD-61753: A. Barber et al., Br. J. Pharmacol., Vol. 113, pp. 1317-1327, 1994. Some of them actually have been studied in clinical trials (Med. Res. Rev., Vol. 12, p. 525, 1992).
WO 98/12177, published Mar. 26, 1998, and U.S. Pat. No. 6,031,114 refer to a method for preparing pyrrolidinyl hydroxamic acid derivatives related to the compounds prepared by the present invention, which are useful as analgesic, antiinflammatory or neuroprotective agents. Each of the foregoing United States patent and PCT international application are incorporated herein by reference in its entirety.
European Patent No. EP 0254545 B1 discloses a variety of ethylenediamine compounds which are related to the compounds prepared by the present method. European Patent No. EP 0483580 B1 discloses a variety of pyrrolidine compounds as analgesics. International Patent Publication WO 96/30339, published Oct. 3, 1996, refers to a wide variety of pyrrolidinyl hydroxamic acid compounds as selective kappa-receptor agonists.
The present invention provides several enhancements over the methods set forth in WO98/12177 and U.S. Pat. No. 6,031,114 for preparing hydroxypyrrolidinyl ethylamine compounds. These enhancements include (1) better control of epimerization at labile optical centers in the conversion steps from benzoic acid pyrrolidiny-3-yl ester to benzoic acid 1-(2-chloro-2-phenylethyl)pyrrolidin-3-yl ester and (2) the avoidance of methyl ether impurities in the conversion steps to the end-stage benzoic acid hydrolysis. These two deficiencies of the above methods significantly diminish the selectivity and the efficiency of the conversion to the desired hydroxypyrrolidinyl ethylamine compounds.
The present invention provides a process of preparing a compound having the formula I: 
or an optical isomer or racemic or optically active mixture of two or more stereoisomers thereof, wherein Ar1 is phenyl optionally substituted by one or more substituents, preferably from one to two substituents, independently independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkoxy, CF3, carboxy-C1-C4 alkoxy and C1-C4 alkoxy-carbonyl-C1-C4 alkoxy;
Ar2 is aryl selected from phenyl and naphthyl, or heteroaryl selected from pyridyl, thienyl, furyl, pyrrolyl and pyrimidyl, the aryl or heteroaryl being optionally substituted by one or more substituents, preferably from one to two substituents, independently selected from halo, hydroxy, amino, nitro, carboxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, halo C1-C4 alkyl, C1-C4 alkylthio and sulfonyl methyl;
R1 is hydrogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy or OY wherein Y is a hydroxy protecting group; and
R2 and R3 are independently selected from hydrogen; hydroxy; C1-C7 alkyl optionally substituted by one or more substituents, preferably one, two or three substituents, independently selected from hydroxy and halo; C3-C6 cycloalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C1-C7 alkoxy; and phenyl optionally substituted by one or more substituents, preferably one, two or three substituents, selected from halo, phenyl C1-C7 alkyl, halo substituted phenyl C1-C7 alkyl, and (CH2)nXxe2x80x94R0 wherein n is one or two;
X is O, NH or S; and
R0 is C1-C3 alkyl, or when Ar2 is phenyl, xe2x80x94Ar2xe2x80x94C(xe2x95x90O)xe2x80x94N(R2)xe2x80x94 is a phthalimide group and R3 is C1-C7 alkyl; or
R2 and R3, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, optionally substituted by one, two or three substituents independently selected from C1-C3 alkyl or halo;
which comprises (a) treating a compound having the formula II: 
wherein Ar1, Ar2, R1, R2, and R3 are as defined above and R4 is C1-C4 alkyl(Cxe2x95x90O)xe2x80x94, aryl(Cxe2x95x90O)xe2x80x94, NH2(Cxe2x95x90O)xe2x80x94, tri(C1-C4 alkyl)silyl, or triarylsilyl, and having the same stereochemical configuration at corresponding chiral centers as the desired compound of formula I, with a base in the presence of an alkyl alcohol and (b) isolating in crystalline form the compound of formula I. In one embodiment of said process of preparing the compound of formula I, the base is an aqueous hydroxide base and the alkyl alcohol is methanol or ethanol. Preferably, R4 is Bz, and the compound of formula II is treated with aqueous sodium hydroxide in the presence of methanol. More preferably, the reaction mixture of the compound of formula II and an aqueous hydroxide base is subsequently treated with benzoic acid prior to isolation of the compound of formula I.
In a further aspect of the present invention, the above process further comprises forming a pharmaceutically acceptable salt of the compound having the formula: 
or an optical isomer or racemic or optically active mixture of two or more stereoisomers thereof, wherein Ar1, A2, R1, R2, and R3 are as defined above. Examples of such pharmaceutically acceptable salts are those selected from the group consisting of, but not limited to, hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, p-toluenesulfonate, oxalate and pamoate (1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The salt is preferably a benzoate salt.
Compounds that may be prepared by the process of present invention include:
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-2-methoxy-Nxe2x80x2-propylbenzamide;
6-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-propylnicotinamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-(2-(S)-hydroxypropyl)benzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-isopropylbenzamide;
3-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-propylbenzamide;
2-chloro-4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-3-methoxy-Nxe2x80x2-propylbenzamide;
3-chloro-4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-propylbenzamide;
4-{N-{1-(S)-(3-hydroxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl}-N-methylamino}-Nxe2x80x2-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-(3-methoxyphenyl)-ethyl}-N-methylamino}-Nxe2x80x2-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(R)-phenylethyl}-N-methylamino}-Nxe2x80x2-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-pyrrolidinebenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-morpholinebenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-(2-(R)-hydroxypropyl)benzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-isobutylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-allylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-phenylethyl}-N-methylamino}-Nxe2x80x2-(3,3,3-trifluoropropyl)benzamide;
3-fluoro-4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-(2,2,3,3,3-pentafluoropropyl)benzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-tert-amylbenzamide;
5-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-propylpicolinamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-methylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-ethylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-butylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-pentylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-phenylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-(2-chlorobenzyl)benzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2,Nxe2x80x2-di-methylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-methyl-Nxe2x80x2-propylbenzamide;
5-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-N xe2x80x2-propyl-2-thiophenecarboxamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}amino}-Nxe2x80x2-propylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-propylphthalimide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-ethoxybenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-(3-hydroxypropyl)benzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-cyclopropylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-(S)-sec-butylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-(R)-sec-butylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-propargylbenzamide;
4-{N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}-N-methylamino}-Nxe2x80x2-tert-butylbenzamide; and
4-{N-hydroxy-N-{2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl}amino}-Nxe2x80x2-propylbenzamide.
The present invention also provides a process of preparing a compound having the formula II: 
or an optical isomer or racemic or optically active mixture of two or more stereoisomers thereof, wherein Ar1 is phenyl optionally substituted by one or more substituents, preferably from one to two substituents, independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkoxy, CF3, carboxy-C1-C4 alkoxy and C1-C4 alkoxy-carbonyl-C1-C4 alkoxy;
Ar2 is aryl selected from phenyl and naphthyl, or heteroaryl selected from pyridyl, thienyl, furyl, pyrrolyl and pyrimidyl, the aryl or heteroaryl being optionally substituted by one or more substituents, preferably from one to two substituents, independently selected from halo, hydroxy, amino, nitro, carboxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di(C1-C4 alkyl)amino, halo C1-C4 alkyl, C1-C4 alkylthio and sulfonyl methyl;
R1 is hydrogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy or OY wherein Y is a hydroxy protecting group; and
R2 and R3 are independently selected from hydrogen; hydroxy; C1-C7 alkyl optionally substituted by one or more substituents, preferably one, two or three substituents, independently selected from hydroxy and halo; C3-C6 cycloalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C1-C7 alkoxy; and phenyl optionally substituted by one or more substituents, preferably one, two or three substituents, selected from halo, phenyl C1-C7 alkyl, halo substituted phenyl C1-C7 alkyl, and (CH2)nXxe2x80x94R0 wherein n is one or two; or
R2 and R3, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, optionally substituted by C1-C3 alkyl or halo;
X is O, NH or S; and
R0 is C1-C3 alkyl, or when Ar2 is phenyl, xe2x80x94Ar2xe2x80x94C(xe2x95x90O)xe2x80x94N(R2)xe2x80x94 is a phthalimide group and R3 is C1-C7 alkyl; and
R4 is C1-C4 alkyl(Cxe2x95x90O)xe2x80x94, aryl(Cxe2x95x90O)xe2x80x94, NH2(Cxe2x95x90O)xe2x80x94, tri(C1-C4 alkyl)silyl, or triarylsilyl;
which comprises reacting a compound having the formula III: 
wherein Ar2, R1, R2, and R3 are as defined above, with a compound having the formula IV: 
wherein Ar1 and R4 are as defined above, and having the same stereochemical configuration at corresponding chiral centers as the desired compound of formula II; and X is hydroxy, C1-C4 alkoxy, fluorine, chlorine, bromine or iodine. Preferably, the process is performed using a compound of the formula IV wherein X is chlorine, and R4 is Bz.
In one embodiment of the present invention, the compound having the formula III, wherein Ar2, R1, R2, and R3 are as defined above, is formed by reacting a compound having the formula V: 
wherein Ar2 and R1 are as defined above, with a compound having the formula VI: 
wherein R2 and R3 are as defined above, in the presence of a condensing agent.
In said process of preparing the compound of formula III, said condensing agent is preferably selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N,Nxe2x80x2-diisopropylcarbodiimide and N,Nxe2x80x2-dicyclocarbodiimide.
The present invention also provides a process of preparing a compound having the formula IV: 
or an optical isomer or racemic or optically active mixture of two or more stereoisomers thereof, wherein Ar1 is phenyl optionally substituted by one or more substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkoxy, CF3, carboxy-C1-C4 alkoxy and C1-C4 alkoxy-carbonyl-C1-C4 alkoxy; R4 is as defined above, and X is hydroxy,
which comprises reacting a compound of formula VII: 
having the same stereochemical configuration at the carbon to which the R4O group is attached as at the corresponding chiral center in the desired compound of formula IV, or an acid addition salt thereof, and wherein R4 is as defined above, with a compound of formula VIII: 
wherein Ar1 is as defined as above, and having the same stereochemical configuration at the carbon to which Ar1 is attached as the corresponding chiral center in the desired compound of formula IV.
The present invention provides a process of preparing a compound having the formula IV: 
or an optical isomer or racemic or optically active mixture of two or more stereoisomers thereof, wherein Ar1 is phenyl optionally substituted by one or more substituents independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkoxy, CF3, carboxy-C1-C4 alkoxy and C1-C4 alkoxy-carbonyl-C1-C4 alkoxy; and X is fluorine, chlorine, bromine or iodine;
which comprises contacting a compound of the formula IVa: 
wherein Ar1 and R4 are as defined above, and having the same stereochemical configurations as the compound of formula IV, with a reagent selected from the group consisting of a p-toluenesulfonyl halide and a methanesulfonyl halide in the presence of a base. Preferably, Ar1 is phenyl, and R4 is Bz.
In said process of preparing the compound of formula IV, said base is preferably selected from the group consisting of triethylamine, trimethylamine, diethylmethylamine, and diethylisopropylamine. Preferably, the process of the present invention is performed wherein X is chlorine, and the reagent is methanesulfonyl chloride (MsCl).
The present invention further provides a process of preparing in crystalline form a compound having the formula Ia: 
or an optical isomer or racemic or optically active mixture of two or more stereoisomers thereof, wherein Ar1 is phenyl optionally substituted by one or more substituents independently selected from halo, C1-C4 alkyl, and CF3;
Ar2 is phenyl, optionally substituted by one or more substituents independently selected from halo and C1-C4 alkyl;
R1 is hydrogen or C1-C4 alkyl; and
R2 and R3 are independently selected from hydrogen; C1-C7 alkyl optionally substituted by one or more halo; C3-C6 cycloalkyl; and phenyl optionally substituted by halo, phenyl C1-C7 alkyl, halo substituted phenyl C1-C7 alkyl, and (CH2)nXxe2x80x94R0 wherein n is one or two;
X is O, NH or S; and
R0 is C1-C3 alkyl, or when Ar2 is phenyl, xe2x80x94Ar2xe2x80x94C(xe2x95x90O)xe2x80x94N(R2)xe2x80x94 is a phthalimide group and R3 is C1-C7 alkyl; or
R2 and R3, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, optionally substituted by one, two or three substituents independently selected from C1-C3 alkyl or halo,
which comprises (a) treating a compound having the formula IIa: 
having the same stereochemical configurations at the corresponding chiral centers as the desired compound of formula Ia, wherein Ar1, Ar2, R1, R2, and R3 are as defined above for compounds of formula I, and R4 is C1-C4 alkyl(Cxe2x95x90O)xe2x80x94, aryl(Cxe2x95x90O)xe2x80x94, NH2(Cxe2x95x90O)xe2x80x94, tri(C1-C4 alkyl)silyl, or triarylsilyl; with a base in the presence of an alcohol selected from methanol and ethanol, and (b) isolating in crystalline form the compound of formula Ia. Preferably, R4 is Bz, and the base used is an aqueous hydroxide base. More preferably, the base is aqueous lithium hydroxide or sodium hydroxide, and the alcohol is methanol. In a preferred aspect of the invention, the process may further comprise contacting the reaction mixture with benzoic acid after treatment with the base.
The process of the present invention further comprises forming a salt of the compound having the formula Ia: 
or an optical isomer isomer or racemic or optically active mixture of two or more stereoisomers thereof, wherein Ar1, Ar2, R1, R2, and R3 are as defined above for compounds of formula I, said salt being selected from the group consisting of hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, p-toluenesulfonate, oxalate and pamoate (1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
The hydroxypyrrolidinyl ethylamine compounds prepared in accordance with the process of the present invention of formula I exhibit good kappa-receptor agonist activity, and thus are useful as analgesic, anesthetic, anti-inflammatory or neuroprotective agents, and also useful in the treatment of arthritis, stroke, or abdominal pain, for the treatment of a mammalian subject, especially a human subject. Specifically, these compounds are useful as analgesic agents for acute and chronic pain. Also, the compounds are useful as analgesic agents for peripheral mediated inflammatory pain caused, for example, by burns (induced by a contact with heat, acid or the other agents), scald (induced by a contact by hot liquid or steam), rheumatism or the like, in the subject.
The compounds prepared by the process of the present invention also are useful for the treatment of a medical condition for which agonist activity toward opioid kappa-receptor is needed, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of the compound of the formula I.
In this specification, the term xe2x80x9chydroxy protecting groupxe2x80x9d means a functional group to protect a hydroxy group against undesirable reactions during synthetic procedures, including, but not limited to benzyl, benzoyl, methoxymethyl, tetrahydropyranyl and trialkylsilyl. (See, for example, T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, New York, Wiley, 1999).
The term xe2x80x9cC1-C6 alkylxe2x80x9d as used herein means a straight or branched alkyl including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like.
The term xe2x80x9cC2-C6 alkenylxe2x80x9d as used herein means a straight or branched alkenyl including but not limited to ethenyl, 2-propenyl, 2-methyl-2-propenyl, 2-butenyl, 2,3-dimethylbut-2-enyl and the like.
The term xe2x80x9cC2-C6 alkynylxe2x80x9d as used herein means a straight or branched alkyl including but not limited to ethynyl, propynyl, 2-butynyl, 2-methylbut-3-ynyl, and the like.
The term xe2x80x9cC3-C6 cycloalkylxe2x80x9d as used herein means a cyclized alkyl ring including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl and the like.
The term xe2x80x9cC1-C6 alkoxyxe2x80x9d as used herein to mean a straight or branched xe2x80x94OR (R is C1-C6 alkyl) including, but not limited to, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy and the like.
The term xe2x80x9chaloxe2x80x9d means F, Cl, Br or I.
The term xe2x80x9chalo C1-C6 alkylxe2x80x9d means a straight or branched, halo-substituted alkyl of 1 to 6 carbon atoms, including, but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl and tert-butyl, substituted by 1 to 13 (preferably one to five) halogen atoms.
The term xe2x80x9chalo C1-C6 alkoxyxe2x80x9d means C1-C6 alkoxy substituted by 1 to 13 (preferably one to three) halogen atoms.
The term xe2x80x9chalo substituted phenyl C1-C7 alkylxe2x80x9d means C1-C7 alkyl having a phenyl group attached to its terminal carbon atom, the phenyl group being substituted by one to five (preferably one to two) halogen atoms.
The term xe2x80x9cone or more substituentsxe2x80x9d as used herein refers to at least one and up to the maximum number of substituents possible in view of the molecular bonding and structure.
More specifically, embodiments of the invention relate to the above processes for preparing compounds of the formula I wherein:
Ar1 is phenyl optionally substituted by one to three substituents independently selected from halo, hydroxy, C1-C4 alkoxy, carboxy C1-C4 alkoxy and C1-C4 alkoxy-carbonyl-C1-C4 alkoxy;
Ar2 is phenyl, pyridyl or thienyl, optionally substituted by one to two three substituents independently selected from halo and C1-C4 alkoxy;
R1 is hydrogen, hydroxy or C1-C4 alkyl; and
R2 and R3 are independently selected from hydrogen; C1-C7 alkyl optionally substituted by one or more substituents, preferably one, two or three substituents, independently selected from hydroxy and halo; C3-C6 (preferably C3-C4) cycloalkyl; C2-C6 alkenyl; C2-C6 (preferably C2-C3) alkynyl; C1-C7 alkoxy; and phenyl optionally substituted by one or more substituents, preferably one, two or three substituents, independently selected from halo, phenyl C1-C7 alkyl, halo substituted phenyl C1-C7 alkyl, and (CH2)nXxe2x80x94R0 wherein n is one or two;
R0 is C1-C3 alkyl, or when Ar2 is phenyl, xe2x80x94Ar2xe2x80x94C(xe2x95x90O)xe2x80x94N(R2)xe2x80x94 is a phthalimide group and R3 is C1-C7 alkyl; or
R2 and R3, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, optionally substituted by C1-C3 alkyl or halo.
Furthermore, other more specific embodiments of the invention relate compounds of formula I wherein:
Ar1 is phenyl optionally substituted by one or more substituents, preferably one, two or three substituents, independently selected from chlorine, hydroxy, methoxy and carboxymethoxy;
Ar2 is phenyl, pyridyl or thienyl, optionally substituted by one or more substituents, preferably one, two or three substituents, independently selected from chlorine, fluorine and methoxy;
R1 is C1-C4 alkyl;
R2 is C1-C7 (preferably C1-C5) alkyl optionally substituted by one or more substituents, preferably one, two or three substituents, independently selected from hydroxy and fluorine; C2-C6 (preferably C2-C3) alkenyl; halo substituted phenylmethyl; and phenyl; and
R3 is hydrogen or methyl; or
R2 and R3, together with the nitrogen atom to which they are attached, form a pyrrolidine or morpholine ring.
Other more specific embodiments of the invention relate compounds of formula I wherein
Ar1 is phenyl optionally substituted by one or more substituents, preferably one, two or three substituents, selected from carboxymethoxy;
Ar2 is phenyl optionally substituted by one or more substituents, preferably one, two or three substituents, independently selected from methoxy and pyridyl;
R1 is C1-C4 alkyl;
R2 is C1-C7 alkyl optionally substituted one, two or three hydroxy groups; and R3 is hydrogen.
The kappa agonists (kappa-receptor agonists) of formula I of this invention can be prepared as described in the following scheme. Unless otherwise indicated, in the reaction schemes that follow, A, Ar1, A2, R1, R2, R3 and R4 are defined as above in the definition of compounds of formula I. 
As shown in Scheme I, an optionally substituted styrene oxide VIII may be reacted with a pyrrolidinyl benzoate of formula VII in the absence or presence of a base such as aqueous sodium hydroxide or K2CO3 to form a substituted pyrrolidinyl ethanol of formula IV wherein X is hydroxy. This reaction may be carried out in the absence or presence of a reaction inert solvent (e.g., methanol (MeOH), ethanol (EtOH), isopropylalcohol, tetrahydrofuran (THF), dioxane, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride (CH2Cl2), water, benzene, toluene, n-hexane or cyclohexane). This reaction can be carried out at a temperature from about xe2x88x9278xc2x0 C. to about the reflux temperature of the solvent, preferably at from about room temperature to about the reflux temperature of the solvent, for a time period ranging from about 5 minutes to about 48 hours, preferably from about 0.5 to about 12 hours. The compound of formula IV wherein X is hydroxy or C1-C4 alkoxy can be treated with a methanesulfonyl halide, preferably methanesulfonyl chloride, or a toluenesulfonyl halide in the presence of a base such as triethylamine in a proper solvent such as dichloroethane, followed by coupling with a benzamide of formula III to give an intermediate compound of formula II. This coupling reaction can be carried out, in the absence or presence of a base such as sodium hydride (NaH), in a suitable polar solvent such as water, EtOH or DMF, at from about room temperature to the reflux temperature of the solvent, for 15 minutes to 24 hours.
The intermediate compound of formula II is then contacted with an aqueous base such as sodium hydroxide or lithium hydroxide in the presence of an alkyl alcohol and water to afford the hydroxypyrrolydinyl ethylamine compound of formula I. Preferred reagents include lithium hydroxide in the presence of methyl alcohol and water. Appropriate solvents are water, tetrahydrofuran, methanol, ethanol, isopropanol, and mixtures thereof. The reaction may take place at a temperature in the range from xe2x88x9230 to 100xc2x0 C., usually from 25 to 60xc2x0 C. for 30 minutes to 24 hours, usually 4 to 12 hours at about 55xc2x0 C. Advantageously, the reaction mixture is treated with a carboxylic acid dissolved or suspended in an alcoholic solvent at a temperature in the range from xe2x88x9230 to 100xc2x0 C., preferably from 10 to 50xc2x0 C. for 30 minutes to 24 hours, and then cooled for about 4 to 12 hours at a temperature in the range from 10 to 30xc2x0 C., preferably from 15 to 25xc2x0 C., and most preferably at about 20xc2x0 C. Preferably, the carboxylic acid is benzoic acid, and the solvent is isopropyl alcohol/water. The resulting product can be isolated as pure crystalline material.
The compounds of formula I prepared by the novel process of this invention are basic, and therefore they will form acid-addition salts. All such salts are within the scope of this invention. However, it is necessary to use an acid addition salt which is pharmaceutically-acceptable for administration to a mammal. The acid-addition salts can be prepared by standard methods, e.g., by contacting the basic and acidic compounds in substantially equivalent proportions in water or an organic solvent such as methanol or ethanol, or a mixture thereof. The salts can be isolated by evaporation of the solvent. Typical salts which can be formed are the hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, p-toluenesulfonate, oxalate and pamoate (1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphtoate)) salts.
The kappa agonists compounds prepared by the processes of the present invention exhibit significant agonist activity toward opioid kappa-receptor and are thus useful as an analgesic, anesthetic, anti-inflammatory agent or neuroprotective agent, and also useful in the treatment of arthritis, stroke or functional bowel disease such as abdominal pain, for the treatment of a mammalian subject, especially a human subject.
The activity of the kappa-agonists compounds of formula I prepared by the process of the present invention is demonstrated by the opioid receptor binding activity. Such activity may be determined in homogenate from guinea pig whole brain, as described by Regina, A. et al., in J. Receptor Res., Vol. 12: pp. 171-180, 1992. In summary, tissue homogenate is incubated at 25xc2x0 C. for 30 min in the presence of labelled ligand and test compounds. The mu-sites are labelled by 1 nM of (3H)-[D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), the delta-sites by 1 nM of (3H)-[D-Pen2,5]enkephalin (DPDPE) and the kappa-sites by 0.5 nM (3H)-Cl-977. The non specific binding is measured by use of 1 xcexcM Cl-977 (kappa), 1 xcexcM (DAMGO) (mu), 1 xcexcM (DPDPE) (delta). Data are expressed as the IC50 values obtained by a non-linear fitting program using the Cheng and Prusoff equation. Some compounds prepared in the Examples showed a potent IC50 value against kappa receptor in the range of 0.01 to 100 nM.
The analgesic activity in the central nervous system of the kappa-agonist compounds prepared by the process of the present invention can also be demonstrated by the Formalin Test as described by Wheeler-Aceto, H. et al. in Psychopharmacology, Vol. 104: pp. 35-44, 1991. In this testing, male SD rats (80-100 g) are injected s.c. with a test compound dissolved in 0.1% methyl cellulose saline or vehicle. After 30 min., 50 xcexcl of a 2% formalin are injected into a hind paw. The number of licking the injected paw per observation period is measured 15-30 min. after the injection of formalin and expressed as % inhibition compared to the respective vehicle group. Some compounds prepared in the Examples showed a potent ED50 value in the range of less than 25 mg/kg p.o.
The activity of the kappa agonists prepared as disclosed herein against peripheral acute-pain can be demonstrated by the Randall-Selitto assay (M. E. Planas, Pain, Vol.60, pp. 67-71, 1995). In this testing, male SD rats (100-120 g) were used and the nociceptive threshold at the right paw was measured by Randall-Selitto (Ugo Basile) method. After three days of acclimation of assay condition, experiments were carried out. Hyperalgesia was induced by the intraplantar injection of a 0.1 ml/right paw of 1% solution of carrageenin. Painful pressure were delivered to the right plantar via a wedge-shaped piston and the level of response were measured at 3.5 and 4.5 hr later the carrageenin injection. Some compounds, prepared in the working examples as described below, were tested in accordance with the above procedures, and showed good activity against acute-pain (i.e., ED50 value of less than 10 mg/kg p.o.).
The activity of the kappa agonists against chronic pain at the periphery can be demonstrated by the adjuvant-induced hyperalgesia, according to the procedure described by Judith S. Waker et al., as reported in Life Sciences, Vol. 57, PP. 371-378, 1995. In this testing, male SD rats weighing 180-230 g at the time of inoculation were used. To produce adjuvant arthritis, rats were anesthetized with ether and inoculated intradermally into the footpad of the right hindpaw with 0.05 ml of Mycobacterium butyricum suspended in paraffin oil (2 mg/ml). Nociceptive threshold was evaluated by paw pressure test, using the same procedures of the Randall-Selitto assay (as described above), and edema was measured as the width of foot. Assays were done through the whole period.
The sedation function of kappa agonists prepared by the process of the invention can be determined by the Rotarod Test as described by Hayes, A. G. et al. in Br. J. Pharmacol., Vol. 79, pp. 731-736, 1983. In this testing, a group of 6-10 male SD rats (100-120 g) are selected for their ability to balance on a rotating rod (diameter 9 cm, rate of rotation 5 r.p.m.). The selected rats are then injected s.c. with a test compound dissolved in 0.1% methyl cellulose saline. The animals are tested again 30 min. after treatment; a rat falling off the bar more than twice within 150 seconds is considered to be showing motor impairment and the animal""s performance (i.e., time on the rotarod) are recorded. The ED50 value is defined as the dose of the drug which has the performance time observed in the control group. Some compounds prepared in the working examples as described below were tested in accordance with the above procedures.
The diuresis function of the kappa agonists can be determined according to the procedure described by A. Barber et al., (Br. J. Pharmacol., Vol. 111, pp. 843-851, 1994). Some compounds, prepared in the working examples as described below, were tested in accordance with the above procedures.
The kappa agonists compounds of formula I prepared by the process of the present invention can be administered via either the oral, parenteral or topical routes to mammals. A preferable dosage level may be in a range of from 0.01 mg to 10 mg per kg of body weight per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. However, a dosage level that is in the range of from 0.01 mg to 1 mg per kg of body weight per day, single or divided dosage is most desirably employed in humans for the treatment of pain in a postoperative patient and a pain like hyperalgesia caused by chronic diseases.
The compounds prepared by the process of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, these therapeutic agents can be administered in a wide variety of different dosage forms; i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, trochees, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds prepared by the process of the invention are present in such dosage forms at concentration levels ranging 5% to 70% by weight, preferably 10% to 50% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene grycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound prepared by the process of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Additionally, it is also possible to administer the compounds prepared by the process of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.